10月12日出版的《美国医学会杂志》发表的一项研究显示，BRCA2基因突变似乎可给卵巢癌患者带来生存优势。
![Figure 1. Functional domains of the BRCA2 protein. The diagram shows the C-terminal nuclear localisation signal and N-terminal transcriptional activation domain; the latter interacts with P/CAF (p300/CBP-associated factor). Binding to the repair protein Rad51 is mediated by BRC repeats. Mutations in the ovarian cancer cluster regions (OCCRs) have been suggested to increase the risk of ovarian, but not breast, cancer; however, this remains controversial. Modified figure reproduced, with permission from Elsevier Science, from Ref. 11 [Welcsh, P.L, Owens, K.N. and King, M.C. (2000) Insights into the functions of BRCA1 and BRCA2. Trends in Genetics 16, 69-74, PubMed] (fig001mgb).](https://pic.biodiscover.com/uploads/5ef059938ba799aaa845e1c2e8a762bd/article/biodiscover_a4dbb9a2887af84118.gif)
BRCA2基因的蛋白功能域
既往研究显示，携带BRCA1或BRCA2突变基因的女性罹患卵巢癌风险较高，但有关确诊患者预后的研究结果却并不一致。部分研究发现突变基因携带者具有更好的预后，而其他研究的结果却截然相反。此外，上述研究均没有对BRCA1和BRCA2突变基因携带者区分分析。为评估两种基因突变分别与生存率的相关性，德州大学M.D. Anderson癌症中心的Da Yang博士及其同事利用癌症基因组图谱(TCGA)数据库，对316例高分级浆液性卵巢癌患者的基因组和临床数据进行了分析。所有肿瘤均为Ⅲ 或Ⅳ期，大多数受试者(86%)为非德系犹太白人，7%为德系犹太人，3%为非裔美国人，3%为亚裔。他们均接受以铂类为基础的辅助治疗，9%还接受紫杉烷类治疗。
结果显示，29例(9.2%)患者携带BRCA2突变基因，37例(11.7%)携带BRCA1突变基因，219例为BRCA野生型突变。BRCA2突变基因携带者5年生存率为61%，显著高于野生型BRCA基因突变者(25%)，但BRCA1突变基因携带者生存率(44%)与野生型BRCA基因突变者无显著差异。对治疗应答进一步分析显示，与BRCA1突变和野生型BRCA突变相比，BRCA2突变与化疗应答显著改善和无铂治疗持续时间延长相关。此外，全部外显子突变数据显示，与BRCA1突变基因不同，BRCA2突变基因含有明显较多的突变位点，表现为“増突表型”。
研究表明，由于两种基因突变性质不同，可能导致患者对以铂类为基础的治疗应答不同，进而表现出生存率相关指标的差异。BRCA2基因突变可能通过提高化疗敏感性和治疗应答率而改善生存。虽然BRCA1和BRCA2在DNA损伤修复方面均起关键作用，但它们似乎具有不同但互补的功能。
哥伦比亚大学综合癌症中心医学部Victor R. Grann博士和Ramon E. Parsons博士在随刊述评中指出，上述发现对改进BRCA基因突变的卵巢癌患者的药物治疗具有重大意义。BRCA1和BRCA2突变基因携带者在治疗应答方面的差异，将有助于开发更好的靶向治疗药物(JAMA 2011;306:1597-8)。
研究者认为，虽然该研究的受试人群具有迄今最为全面的资料(包括基因组和临床资料)，但队列仍相对较小，研究结果尚需进一步研究证实。
该研究由美国国立卫生研究院(NIH)、Blanton-Davis卵巢癌研究项目和卵巢癌SPORE基金资助。研究者无利益冲突报告。
相关英文论文摘要：
Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer
Context Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer have produced conflicting results.
Objective To determine the relationships between BRCA1/2 deficiency (ie, mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole-exome mutation rate in ovarian cancer.
Design, Setting, and Patients Observational study of multidimensional genomics and clinical data on 316 high-grade serous ovarian cancer cases that were made public between 2009 and 2010 via The Cancer Genome Atlas project.
Main Outcome Measures OS and PFS rates (primary outcomes) and chemotherapy response (secondary outcome).
Results BRCA2 mutations (29 cases) were associated with significantly better OS (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16-0.69; P = .003 and 5-year OS, 61% for BRCA2-mutated vs 25% for BRCA wild-type cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22-0.74; P = .004 and 3-year PFS, 44% for BRCA2-mutated vs 16% for BRCA wild-type cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) was associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2-mutated vs 82% [P = .02] and 80% [P = .05] for BRCA wild-type and BRCA1-mutated cases, respectively) and longer platinum-free duration (median platinum-free duration, 18.0 months for BRCA2-mutated vs 11.7 [P = .02] and 12.5 [P = .04] months for BRCA wild-type and BRCA1-mutated cases, respectively). BRCA2-mutated, but not BRCA1-mutated cases, exhibited a “mutator phenotype” by containing significantly more mutations than BRCA wild-type cases across the whole exome (median mutation number per sample, 84 for BRCA2-mutated vs 52 for BRCA wild-type cases, false discovery rate <0.1).
Conclusion Among women with high-grade serous ovarian cancer, BRCA2 mutation, but not BRCA1 deficiency, was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type.
英文论文链接：https://jama.ama-assn.org/content/306/14/1557.full?sid=b0ff2169-7b95-4cbc-b72d-7a6ca90657e2
